Pulmonary Vasoconstrictor Response Research Articles

Intravenous iron loading inhibits the pulmonary vascular response to hypoxia in humans

Aim: To manipulate the hypoxia-inducible factor (HIF) transcription factors pharmacologically and thereby confirm that HIF regulates human pulmonary vascular responses to hypoxia. Background: HIF controls intracellular responses to hypoxia, and our recent work strongly implicates HIF in regulating human heart/lung physiology (Smith et al. PLoS Med 2006; 3: ). Iron is an obligate co-factor in the degradation pathway through which HIF is primarily regulated, and iron supplementation potentiates HIF degradation in vitro. Hypothesis: Supraphysiological levels of iron similarly augment HIF degradation in vivo and thus inhibit acclimatisation to hypoxia. Methods: Six normal subjects were each studied on two days. Day 1 (control) began with an infusion of saline while on Day 2 it was 200 mg iron sucrose. On each day subjects then underwent: a 40-min acute isocapnic hypoxia protocol (end-tidal PO2 50 mmHg), with pulmonary vascular tone assessed echocardiographically; 8 h of isocapnic hypoxia in a chamber; repeat of the acute hypoxia protocol. Results: Iron loading prevented the rise in pulmonary arterial pressure normally present after sustained hypoxia and blunted acclimatisation of the acute hypoxic pulmonary vasoconstrictive response (p < 0.01; Fig 1). Conclusions: HIF degradation is limited by physiological levels of iron, and HIF appears to control human pulmonary vascular responses to hypoxia. Funded by the Wellcome Trust. TGS is supported by a Rhodes Scholarship.

Classical transient receptor potential channel 6 (TRPC6) is essential for hypoxic pulmonary vasoconstriction and alveolar gas exchange

Regional alveolar hypoxia causes local vasoconstriction in the lung, shifting blood flow from hypoxic to normoxic areas, thereby maintaining gas exchange. This mechanism is known as hypoxic pulmonary vasoconstriction (HPV). Disturbances in HPV can cause life-threatening hypoxemia whereas chronic hypoxia triggers lung vascular remodeling and pulmonary hypertension. The signaling cascade of this vitally important mechanism is still unresolved. Using transient receptor potential channel 6 (TRPC6)-deficient mice, we show that this channel is a key regulator of acute HPV as this regulatory mechanism was absent in TRPC6(-/-) mice whereas the pulmonary vasoconstrictor response to the thromboxane mimetic U46619 was unchanged. Accordingly, induction of regional hypoventilation resulted in severe arterial hypoxemia in TRPC6(-/-) but not in WT mice. This effect was mirrored by a lack of hypoxia-induced cation influx and currents in smooth-muscle cells from precapillary pulmonary arteries (PASMC) of TRPC6(-/-) mice. In both WT and TRPC6(-/-) PASMC hypoxia caused diacylglycerol (DAG) accumulation. DAG seems to exert its action via TRPC6, as DAG kinase inhibition provoked a cation influx only in WT but not in TRPC6(-/-) PASMC. Notably, chronic hypoxia-induced pulmonary hypertension was independent of TRPC6 activity. We conclude that TRPC6 plays a unique and indispensable role in acute hypoxic pulmonary vasoconstriction. Manipulation of TRPC6 function may thus offer a therapeutic strategy for the control of pulmonary hemodynamics and gas exchange.

Ischemic preconditioning modulates ischemia-reperfusion injury in the rat lung: Role of adenosine receptors

Recent studies have been focused on the protective role of ischemic preconditioning against ischemia-reperfusion injury of the lung occurring following cardiopulmonary by-pass surgery and lung or heart transplantation. The present study was undertaken to investigate the role of adenosine in ischemic preconditioning in the isolated buffer-perfused rat lung. Since the pulmonary perfusion flow rate and left atrial pressure were constant, changes in pulmonary arterial pressure directly reflect changes in pulmonary vascular resistance. When compared to control values, ischemia-reperfusion injury in the form of 2 h of normothermic ischemia significantly reduced the pulmonary vasoconstrictor response to phenylephrine and KCl, increased wet-to-dry lung weight ratios and increased malondialdehyde content of rat lungs. Ischemic preconditioning in the form of one cycle of 5 min of ischemia and reperfusion applied prior to ischemia-reperfusion, as well as, adenosine preconditioning in the form of adenosine infusion prior to ischemia-reperfusion independently prevented the reduction in pulmonary vasoconstrictor responses and the increases in pulmonary edema and malondialdehyde formation in response to ischemia-reperfusion injury. Pretreatment with adenosine receptor antagonists, theophylline or 8-cyclopentyl-1,3-dipropyl xanthine (DPCPX) prior to ischemic preconditioning or adenosine preconditioning abolished the protective effects of preconditioning by ischemic preconditioning and adenosine preconditioning. The present data demonstrate that ischemic preconditioning and adenosine preconditioning prevent the vascular and biochemical alterations studied in response to ischemia-reperfusion injury in the pulmonary vascular bed of the rat. Results of the present study suggest activation of adenosine A 1 receptors mediates the protective properties of ischemic preconditioning and adenosine preconditioning on ischemia-reperfusion injury in the lung. Moreover, the present data further suggest selective adenosine receptor agonists may be useful as pharmacologic preconditioning agents in preventing ischemia-reperfusion injury in lung transplantation and other forms of pulmonary vascular ischemia.

State of the Art. A structural and functional assessment of the lung via multidetector-row computed tomography: phenotyping chronic obstructive pulmonary disease.

With advances in multidetector-row computed tomography (MDCT), it is now possible to image the lung in 10 s or less and accurately extract the lungs, lobes, and airway tree to the fifth- through seventh-generation bronchi and to regionally characterize lung density, texture, ventilation, and perfusion. These methods are now being used to phenotype the lung in health and disease and to gain insights into the etiology of pathologic processes. This article outlines the application of these methodologies with specific emphasis on chronic obstructive pulmonary disease. We demonstrate the use of our methods for assessing regional ventilation and perfusion and demonstrate early data that show, in a sheep model, a regionally intact hypoxic pulmonary vasoconstrictor (HPV) response with an apparent inhibition of HPV regionally in the presence of inflammation. We present the hypothesis that, in subjects with pulmonary emphysema, one major contributing factor leading to parenchymal destruction is the lack of a regional blunting of HPV when the regional hypoxia is related to regional inflammatory events (bronchiolitis or alveolar flooding). If maintaining adequate blood flow to inflamed lung regions is critical to the nondestructive resolution of inflammatory events, the pathologic condition whereby HPV is sustained in regions of inflammation would likely have its greatest effect in the lung apices where blood flow is already reduced in the upright body posture.

Role of endothelin receptor activation in secondary pulmonary hypertension in awake swine after myocardial infarction

We previously observed that pulmonary hypertension secondary to myocardial infarction (MI) in swine is characterized by elevated plasma endothelin (ET) levels and pulmonary vascular resistance (PVR). Consequently, we tested the hypothesis that an increased ET-mediated vasoconstrictor influence contributes to secondary pulmonary hypertension after MI and investigated the involvement of ET(A) and ET(B) receptor subtypes. Chronically instrumented swine with (MI swine; n = 25) or without (normal swine; n = 19) MI were studied at rest and during treadmill exercise (up to 4 km h(-1)), in the absence and presence of the ET(A) antagonist EMD 122946 or the mixed ET(A)/ET(B) antagonist tezosentan. In normal swine, exercise caused a small decrease in PVR. ET(A) blockade had no effect on PVR at rest or during exercise. Conversely, ET(A)/ET(B) blockade decreased PVR but only during exercise (at 4 km h(-1), from 3.0 +/- 0.1 to 2.3 +/- 0.1 mmHg min l(-1); P <or= 0.05). MI increased pulmonary arterial pressure and PVR both at rest and during exercise (both P <or= 0.05). The increased pulmonary arterial pressure correlated with the increased plasma ET levels in resting MI swine (r = 0.71; P <or= 0.01). Furthermore, the pulmonary vasoconstrictor response to ET-1 infusion was enhanced after MI (P <or= 0.05). ET(A)/ET(B) blockade decreased PVR in MI swine from 3.6 +/- 0.3 to 3.1 +/- 0.5 mmHg min l(-1) at rest and from 3.4 +/- 0.3 to 2.4 +/- 0.2 mmHg min l(-1) during exercise at 4 km h(-1) (both P <or= 0.05). This increased response to mixed ET(A)/ET(B) blockade in MI compared to normal swine appeared to be the result of an increased ET(A)-mediated vasoconstriction, as ET(A) blockade decreased PVR in MI swine from 3.4 +/- 0.4 to 2.8 +/- 0.2 mmHg min l(-1) at rest and from 3.1 +/- 0.3 to 2.6 +/- 0.2 mmHg min l(-1) at 4 km h(-1) (both P <or= 0.05). In conclusion, increased plasma ET levels together with increased pulmonary resistance vessel responsiveness to ET result in an exaggerated pulmonary vasoconstrictor influence of ET in swine with a recent MI. This vasoconstrictor influence is the result of an emergent tonic ET(A)-mediated vasoconstriction in addition to the exercise-induced ET(B)-mediated vasoconstriction that is already present in normal swine.

Integrating Systems Biology and Medical Imaging: Understanding Disease Distribution in the Lung Model

Many chronic diseases exhibit characteristic pulmonary distribution patterns, but the underlying biologic explanations remain elusive. On the basis of emerging evidence from systems biology, we propose that gradients of T helper immune function exist as an epiphenomenon of the hypoxic pulmonary vasoconstriction response. Regional variation of immune function may contribute to preferential distribution patterning of lung diseases. The lungs represent but one example in which the distribution of immune function throughout the body may explain disease location. This hypothetic framework can apply to diseases outside the realm of pulmonary biology and illustrates the potential benefit of integrating advances in systems biology and medical imaging.

The in vivo effects of human urotensin II in the rabbit and rat pulmonary circulation: Effects of experimental pulmonary hypertension

In vivo haemodynamic responses to human urotensin-II were determined in two models of pulmonary hypertension: rabbits with left ventricular dysfunction following coronary artery ligation and the hypoxic rat. Effects were also examined in the presence of the nitric oxide synthase inhibitor N ω-nitro- l-arginine methyl ester ( l-NAME). Human urotensin-II increased pulmonary arterial pressure to a greater extent in ligated rabbits than their controls and l-NAME increased pulmonary pressure without significantly affecting these responses to human urotensin-II. Human urotensin-II raised right ventricular pressure slightly in control rats but not in hypoxic rats. Human urotensin-II did not constrict control rat isolated small pulmonary arteries and only induced a small constriction of these vessels in hypoxic rats. In conclusion, exogenous human urotensin-II exerts pulmonary pressor responses in vivo in rabbits and also induced small pulmonary pressor responses in control rats. Pulmonary pressor responses to urotensin-II were increased by pulmonary hypertension in rabbits but not in rats.

Influence of TMB-8 and Thapsigargin on Vasoconstrictor Responses in the Pulmonary Vascular Bed of the Cat

The effects of 8-(diethylamino)octyl-3,4,5-trimethoxybenzoate hydrochloride (TMB-8), a protein kinase C (PKC) inhibitor, and thapsigargin, a CaATPase inhibitor, on pressor responses were studied in the pulmonary vascular bed of the intact-chest anesthetized cat. Under conditions of constant lobar blood flow in the cat, injections of the angiotensin peptides (ANG II), norepinephrine (NE), serotonin (5-HT), Bay K 8644, and the thromboxane A2 mimic U46619 into the lobar arterial perfusion circuit caused dose-related increases in lobar arterial pressure and responses were reproducible with respect to time. Intravenous infusion of TMB-8 at 1.0 mug . kg reduced the pressor response to the ANG II and to NE. However, TMB-8 did not alter pressor responses to 5-HT, U46619, or Bay K 8644. In a separate series of experiments, the effects of thapsigargin were investigated and intravenous infusion of the CaATPase inhibitor at 1.0 mug . kg also reduced pressor responses to the ANG II and to NE but did not alter pressor responses to 5-HT, U46619, and Bay K 8644. The data provide support for the hypothesis that vasoconstrictor responses to ANG II and NE in the pulmonary vascular bed are mediated in part by the activation of protein kinase C (PKC) and sarcoplasmic reticulum CaATPase-sensitive mechanisms in the cat. The present data suggest that pulmonary pressor responses to U46619, 5-HT, and Bay K 8644 are not mediated by PKC or CaATPase activation in the pulmonary vascular bed of the cat.

Fentanyl Attenuates α1B-Adrenoceptor–Mediated Pulmonary Artery Contraction

The authors tested the hypothesis that the intravenous anesthetic fentanyl would attenuate the pulmonary vasoconstrictor response to alpha1-adrenoceptor activation. They also investigated the alpha1-adrenoceptor subtypes that could potentially mediate this effect of fentanyl. Endothelium-denuded canine pulmonary arterial rings were suspended for isometric tension recording. Dose-response curves for the alpha1-adrenoceptor agonist phenylephrine were generated in the absence and presence of fentanyl. The effects of inhibiting alpha2 (rauwolscine), alpha1 (prazosin), alpha1A (5-methylurapidil), alpha1B (chloroethylclonidine), and alpha1D (BMY 7378) adrenoceptors on phenylephrine contraction were also investigated. Receptor "protection" studies were performed to investigate the specific role of alpha1B adrenoceptors in mediating fentanyl-induced changes in phenylephrine contraction. Finally, competition binding studies were performed in rat-1 fibroblasts stably transfected with human alpha1-adrenoceptor complementary DNAs corresponding to the alpha1A-, alpha1B-, or alpha1D-adrenoceptor subtypes to directly assess whether fentanyl can compete for the alpha1-adrenoceptor activation pocket. Fentanyl attenuated phenylephrine contraction in a dose-dependent fashion. Rauwolscine had no effect on phenylephrine contraction. Phenylephrine contraction was inhibited by prazosin and abolished by chloroethylclonidine but was relatively resistant to inhibition by 5-methylurapidil and BMY 7378. Pretreatment with fentanyl before exposure to chloroethylclonidine increased the maximal contractile response to phenylephrine compared to chloroethylclonidine pretreatment alone. Competition binding studies revealed that fentanyl binds to all three alpha1-adrenoceptor subtypes, with a fivefold greater affinity for the alpha1B-adrenoceptor compared with the alpha1D-adrenoceptor subtype. Phenylephrine-induced contraction is primarily mediated by alpha1B-adrenoceptor activation in canine pulmonary artery. Fentanyl attenuates phenylephrine contraction by binding to alpha1B adrenoceptors.

Pressor Responses to Ephedrine Are Mediated by a Direct Mechanism in the Rat

The mechanism of the pressor response to ephedrine is controversial. In the present study. i.v. injections of ephedrine increased systemic and pulmonary arterial pressure, and i.a. injections decreased hindlimb blood flow in a dose-related manner. Responses to ephedrine were inhibited by alpha-receptor blocking agents and were not attenuated by blockade of the norepinephrine reuptake transporter (NET) or by catecholamine depletion using reserpine or a combination of reserpine and alpha-methyl-p-tyrosine, whereas responses to tyramine and amphetamine were inhibited by these treatments. The magnitude of the pressor response to ephedrine was similar in anesthetized and conscious rats. Tachyphylaxis developed to pressor responses to ephedrine and amphetamine with sequential injections; however, ephedrine tachyphylaxis differed in that subsequent responses to alpha-receptor agonists were attenuated. These results suggest that the systemic and pulmonary pressor and hindlimb vasoconstrictor responses to ephedrine are mediated by direct action on alpha-adrenergic receptors and that the release of norepinephrine from adrenergic terminals plays no significant role. These results provide support for the hypothesis that responses to ephedrine are directly mediated in the intact rat, whereas responses to amphetamine are mediated in a large part by the release of norepinephrine from adrenergic terminals.

Analysis of Pulmonary Vascular Response to Acute Alveolar Hypoxic Challenge in Young Rabbits Subjected to Chronic Hypoxia from Birth

Chronic alveolar hypoxia induces vascular changes leading to pulmonary hypertension. We investigated the role of nitric oxide synthase (NOS) on basal pulmonary artery pressure (PAP) and on changes in PAP arising from an acute alveolar hypoxic challenge (AAHC) in normoxic and chronically hypoxic young rabbits. The chronically hypoxic rabbits were raised from birth in a chamber containing a (10% O2 + 90% N2) gas mixture, whereas the normoxic rabbits were kept in room air. The age of the animals at the time of study (approximately 38 days) was not significantly different between the 2 groups of rabbits. The in vivo PAP was measured using a right heart catheterization technique while the rabbits were spontaneously breathing either a hyperoxic or a hypoxic gas. In the chronically hypoxic group, the AAHC (hypoxic gas) produced a modest increase in PAP. However, after intravenous administration of (100 mg/kg) of the NOS inhibitor, L-NAME (N-nitro-L-arginine methyl ester), a marked increase in PAP was observed when these rabbits were rechallenged with the AAHC. In contrast, in the normoxic rabbits, the AAHC produced only a small increase in PAP, even after pretreatment with L-NAME. In both groups of rabbits, L-NAME led to a significant rise in basal PAP. Using Western blot analysis, we found endothelial NOS (eNOS) protein expression to be significantly increased in pulmonary artery and right ventricular myocardium of the chronically hypoxic rabbits. These results suggest that release of nitric oxide is involved in regulating basal PAP and in modulating the hypoxia-induced pulmonary vasoconstrictor response in immature animals. Moreover, eNOS appears to undergo up-regulation as a consequence of chronic hypoxia.

Vasoactive prostanoids are generated from arachidonic acid by COX-1 and COX-2 in the mouse

Generation of vasoactive prostanoids from arachidonic acid by cyclooxygenase (COX)-1 and COX-2 was investigated in anesthetized mice. Intravenous injections of the prostanoid precursor arachidonic acid increased pulmonary arterial pressure and decreased systemic arterial pressure. Pulmonary pressor and systemic depressor responses were attenuated by SC-560 and nimesulide, inhibitors of COX-1 and COX-2, in doses that did not alter responses to injected prostanoids. Pulmonary pressor responses to arachidonic acid were blocked and a depressor response was unmasked, whereas systemic depressor responses were not altered, by a thromboxane receptor antagonist. Pulmonary and systemic pressor responses to angiotensin II injections and systemic pressor responses to angiotensin II infusion were not modified by COX-1 or COX-2 inhibitors but were attenuated by losartan. Systemic depressor responses to arachidonic acid were smaller in COX-1 and COX-2 knockout mice, whereas responses to angiotensin II, norepinephrine, U-46619, endothelin-1, and PGE(1) were not different in COX-1 and COX-2 knockout and wild-type control mice. These results suggest that vasoactive prostanoids with pulmonary pressor and systemic vasodepressor activity are formed by COX-1 and COX-2 and are consistent with Western blot analysis and immunostaining showing the presence of COX-1 and COX-2. These data suggest that thromboxane A(2) (TxA(2)) is formed from the precursor by COX-1 and COX-2 in the lung and are in agreement with immunofluorescence studies showing thromboxane synthase. The present data suggest that COX-1- or COX-2-derived prostanoids do not modulate responses to angiotensin II or other vasoactive agents and that prostanoid responses are similar in CD-1 and C57BL/6 and in male and female mice.

Role of endogenous nitric oxide in endotoxin-induced alteration of hypoxic pulmonary vasoconstriction in mice

Pulmonary vasoconstriction in response to alveolar hypoxia (HPV) is frequently impaired in patients with sepsis or acute respiratory distress syndrome or in animal models of endotoxemia. Pulmonary vasodilation due to overproduction of nitric oxide (NO) by NO synthase 2 (NOS2) may be responsible for this impaired HPV after administration of endotoxin (LPS). We investigated the effects of acute nonspecific (N(G)-nitro-L-arginine methyl ester, L-NAME) and NOS2-specific [L-N6-(1-iminoethyl)lysine, L-NIL] NOS inhibition and congenital deficiency of NOS2 on impaired HPV during endotoxemia. The pulmonary vasoconstrictor response and pulmonary vascular pressure-flow (P-Q) relationship during normoxia and hypoxia were studied in isolated, perfused, and ventilated lungs from LPS-pretreated and untreated wild-type and NOS2-deficient mice with and without L-NAME or L-NIL added to the perfusate. Compared with lungs from untreated mice, lungs from LPS-challenged wild-type mice constricted less in response to hypoxia (69 +/- 17 vs. 3 +/- 7%, respectively, P < 0.001). Perfusion with L-NAME or L-NIL restored this blunted HPV response only in part. In contrast, LPS administration did not impair the vasoconstrictor response to hypoxia in NOS2-deficient mice. Analysis of the pulmonary vascular P-Q relationship suggested that the HPV response may consist of different components that are specifically NOS isoform modulated in untreated and LPS-treated mice. These results demonstrate in a murine model of endotoxemia that NOS2-derived NO production is critical for LPS-mediated development of impaired HPV. Furthermore, impaired HPV during endotoxemia may be at least in part mediated by mechanisms other than simply pulmonary vasodilation by NOS2-derived NO overproduction.

Postnatal maturational shift from PKC? and voltage-gated K channels to RhoA/Rho kinase in pulmonary vasoconstriction

The neonate is at high risk of developing pulmonary hypertension, which may reflect a misbalance between vasodilator and vasoconstrictor agents. Thromboxane A(2) (TXA(2)) is involved in several forms pulmonary hypertension, but the signaling pathways mediating its pulmonary vasoconstrictor responses during postnatal maturation have not been analyzed. We therefore investigated the role of L-type Ca(2+) channels, protein kinase C (PKC) zeta, voltage-gated K(+) channels (K(V)), and RhoA/Rho kinase in TXA(2)-induced pulmonary vasoconstriction during postnatal maturation. Changes in contractility and intracellular calcium were analyzed in 1 day (newborn) and 2-week-old piglets' pulmonary arteries (PA). K(V) currents were investigated in freshly isolated smooth muscle cells using the whole-cell configuration of the patch clamp technique. The contractile responses to the TXA(2) mimetic U46619 were similar at both ages but the L-type Ca(2+) channel blocker nifedipine and a PKCzeta pseudosubstrate inhibitor only attenuated the contraction in newborn PA. K(V) currents were similarly inhibited by U46619, although their density was dramatically reduced in 2-week-old as compared to newborn PA smooth muscle cells. This was consistent with a greater contraction to the K(V) inhibitor, 4-aminopyridine, and with a leftward shift in the increase in intracellular Ca(2+) by U46619 in newborn versus older animals. On the other hand, the Rho kinase inhibitor Y-27632 induced a stronger inhibitory effect on the contraction induced by U46619 in 2-week-old than in newborn PA and this was accompanied with minor effects on intracellular calcium levels. TXA(2)-induced pulmonary vasoconstriction involves PKCzeta-K(V)-L-type Ca(2+) channel and RhoA/Rho kinase signaling pathways, which are downregulated and upregulated, respectively, during postnatal maturation. The different contribution of these pathways could be of relevant importance for the vasodilator therapy choice in the treatment of pulmonary hypertension.

Effect of normoxia and hypoxia on K+ current and resting membrane potential of fetal rabbit pulmonary artery smooth muscle

At birth, the increase in O(2) tension (pO(2)) is an important cause of the decrease in pulmonary vascular resistance. In adult animals there are impressive interspecies differences in the level of hypoxia required to elicit a pulmonary vasoconstrictor response and in the amplitude of the response. Hypoxic inhibition of some potassium (K(+)) channels in the membrane of pulmonary arterial smooth muscle cells (PASMCs) helps to initiate hypoxic pulmonary vasoconstriction. To determine the effect of the change in pO(2) on fetal rabbit PASMCs and to investigate possible species-dependent differences, we measured the current-voltage relationship and the resting membrane potential, in PASMCs from fetal resistance arteries using the amphotericin-perforated patch-clamp technique under hypoxic and normoxic conditions. Under hypoxic conditions, the K(+) current in PASMCs was small, and could be inhibited by 4-aminopyridine, iberiotoxin and glibenclamide, reflecting contributions by Kv, K(Ca) and K(ATP) channels. The average resting membrane potential was -44.3+/-1.3 mV (n=29) and could be depolarized by 4-AP (5 mM) and ITX (100 nM) but not by glibenclamide (10 microM). Changing from hypoxia, that mimicked fetal life, to normoxia dramatically increased the K(Ca) and consequently hyperpolarized (-9.3+/-1.7 mV; n=8) fetal rabbit PASMCs. Under normoxic conditions K(+) current was reduced by 4-AP with a significant change in resting membrane potential (11.1+/-1.7 mV; n=8). We conclude that resting membrane potential in fetal rabbit PASMCs under both hypoxic and normoxic conditions depends on both Kv and K(Ca) channels, in contrast to fetal lamb or porcine PASMCs. Potential species differences in the K(+) channels that control resting membrane potential must be taken into consideration in the interpretation of studies of neonatal pulmonary vascular reactivity to changes in O(2) tension.

High-Altitude Pulmonary Edema in Children With Underlying Cardiopulmonary Disorders and Pulmonary Hypertension Living at Altitude

Pulmonary hypertension has not been described as a predisposing risk factor for high-altitude pulmonary edema (HAPE) in children. Previous studies have shown an association of HAPE with abnormally increased pulmonary vasoreactivity to hypoxia but generally normal pulmonary artery pressure (PAP) after recovery. To describe HAPE of relatively rapid onset and its management in a series of children residing at moderate to high altitudes, all of whom had underlying pulmonary hypertension. From 1997 to 2003, 30 children came to our center with high-altitude illness. Of these, 10 children (aged 4-18 years; male-female ratio, 8:2) living at moderate to high altitudes (1610-3050 m) underwent cardiac catheterization after recovery from HAPE, and all were found to have chronic pulmonary hypertension (mean PAP, 38 +/- 9 mm Hg; pulmonary vascular resistance, 8.6 +/- 2.8 U x m2). Increases in PAP and pulmonary vascular resistance to hypoxia (16% oxygen) suggest that these children have a reactive pulmonary pressor response and hence are susceptible to HAPE. Six of the 10 patients had predisposing cardiopulmonary abnormalities, and 5 of these 6 patients did not receive a diagnosis prior to the onset of HAPE. Long-term treatment with calcium channel blockers, bosentan, sildenafil citrate, and/or oxygen lowered PAP, improved symptoms, and prevented the recurrence of HAPE. Children living at altitude who develop HAPE should undergo screening for diagnosis of underlying cardiopulmonary abnormalities including pulmonary hypertension.

The Functional Shift of Endothelin Receptor Subtypes in Dogs with Heart Failure Produced by Rapid Ventricular Pacing

To clarify the functional role of endothelin-A/endothelin- B (ETA/ETB) receptors in congestive heart failure (CHF), we examined the effects of a non-selective endothelin receptor agonist, endothelin-1 (ET-1), and a selective ETB receptor agonist, sarafotoxin S6c. CHF was induced in dogs by rapid ventricular pacing and resulted in decreased left ventricular dp/dtmax, decreased cardiac output and increased pulmonary vascular resistance. Sarafotoxin S6c (0.3 nmol/kg) resulted in decreased left ventricular dp/dtmax (-26 +/- 2%), decreased cardiac output (-47 +/- 3%) and increased pulmonary vascular resistance (+48 +/- 10%) in dogs without CHF. The effects of sarafotoxin S6c were attenuated in dogs with CHF (-12 +/- 5% in left ventricular dp/dtmax, -19 +/- 5% in cardiac output and +7 +/- 5% in pulmonary vascular resistance). In contrast, ET-1 (0.5 nmol/kg) had no effect on left ventricular dp/dtmax in dogs without CHF and increased left ventricular dp/dtmax by 16 +/- 3% in dogs with CHF. These data indicate that reduced cardiac contractile and pulmonary vasoconstrictor responses via the ETB receptor are attenuated and that responses mediated by the ETA receptor are more prominent in the context of CHF. This suggests a functional shift of endothelin receptor subtypes in CHF.

Characteristics of the in vitro hypoxic pulmonary vasoconstrictor response in isolated equine and bovine pulmonary arterial rings

ObjectiveHypoxaemia accompanies dorsal recumbency in the horse and frequently complicates general anaesthesia. The physiology associated with this phenomenon is poorly understood. One possible cause of poor tolerance to dorsal recumbency is an absent or reduced response to hypoxic pulmonary vasoconstriction (HPV). This study compared the HPV response in isolated pulmonary artery vessels from equivalent regions of equine and bovine lung. AnimalsEquine and bovine, in vitro study. Materials and methodsEquine and bovine pulmonary arteries were removed from the lungs of euthanased horses and cattle. Measurements of isometric tension were made on isolated rings of pulmonary vessels at 37 °C in a Krebs' saline solution. Hypoxia was induced by bubbling with a nominally 0% O2 gas mixture. ResultsA significant HPV response was observed above a baseline tension induced by phenylephrine (PE; 0.3 μm) or 5-hydroxytryptamine (5-HT; 0.1 μm). The HPV response in equine pulmonary vessels was approximately 33% less than the response observed in equivalent bovine vessels (equine 196 ± 20%versus bovine 290 ± 32%; p < 0.05). Removal of the endothelium (by rubbing the luminal surface) significantly reduced but did not abolish the HPV response. Incubation with the nitric oxide (NO) synthase inhibitor N-nitro-l-arginine methyl ester (L-NAME; 100 μm), or COX-1/COX-2 inhibitor indomethacin (10 μm) markedly attenuated the HPV response in equine vessels. ConclusionsThese results suggest that a significant HPV response exists in isolated equine pulmonary vessels; a component of this response requires a functional endothelium. Inhibition of cyclooxygenase and NO synthase attenuated the response, suggesting the involvement of a COX product and/or NO in mediating this effect either directly or indirectly. Alternatively, a non-COX related action of the nonsteroidal anti-inflammatory drug, indomethacin, may be involved.

The role of 5-hydroxytryptamine in the control of pulmonary vascular tone in a rabbit model of pulmonary hypertension secondary to left ventricular dysfunction

The role of 5-hydroxytryptamine (5-HT) in a rabbit model of pulmonary hypertension (PHT) secondary to left ventricular dysfunction was investigated. Following pulmonary artery catheterisation under anaesthesia, 5-HT (1–400 μg kg −1 i.v.) was administered before and after either 5-HT 2A receptor antagonism with ketanserin (0.5 mg kg −1) or infusion of the nitric oxide synthase inhibitor, l-NAME (30 μmol min −1). Eight week coronary artery ligated rabbits demonstrate increased mean pulmonary arterial pressure (PAP) compared to controls (17.0±0.5 versus 12.0±0.5 mmHg, P<0.001) accompanied by right ventricular hypertrophy. 5-HT alone produced a greater pulmonary pressor response in rabbits with PHT (increase of 7.5±1.2, n=12 c.f. 3.5±0.4 mmHg in shams, n=12, P<0.01). Ketanserin had no effect on basal PAP in either PHT or control rabbits but inhibited the response to 5-HT in both groups. The response to 5-HT following l-NAME was increased in both groups and was greater in rabbits with PHT (an increase of 20.1±2.9, n=6 c.f. 11.4±1.8 mmHg, n=6, P<0.05). These results suggest that the difference shown in the in vivo pulmonary response to exogenous 5-HT is mediated largely through 5-HT 2A receptors in this model. However, activity of endogenous 5-HT at the 5-HT 2A receptors is not responsible for maintaining the raised basal PAP through vasoconstriction in PHT rabbits once PHT has developed.

Endogenous nitric oxide and pulmonary circulation response to hypoxia in high-altitude adapted Tibetan sheep.

Nitric oxide (NO) is important for the pulmonary circulation response to acute and chronic hypoxia. We examined effects of endogenous nitric oxide synthase (NOS) inhibition on pulmonary vascular tone in response to hypoxia in Tibetan sheep dwelling at 3,000 m above sea level using a pressure chamber. Unanaesthetized male sheep living at 2,300 m above sea level ( n=7) were prepared for vascular monitoring. Pulmonary artery ( P(pa)), pulmonary artery wedge ( P(cwp)) and systemic artery pressures together with cardiac output (CO) were measured, and pulmonary vascular resistance (PVR) was calculated as ( P(pa)- P(cwp))/CO. A non-selective NOS inhibitor, N(omega)-nitro- l-arginine (NLA; 20 mg kg(-1)), and a selective NOS inhibitor, ONO-1714 (0.1 mg kg(-1)), were used and measurements were made at 0 m, 2,300 m, and 4,500 m, with and without the NOS inhibitors. After NLA, P(pa) increased slightly and CO decreased in animals at baseline (2,300 m). The increased PVR after NLA at 4,500 m was greater than that at 2,300 m ( P<0.05). Selective NOS inhibition increased PVR at baseline, but not at 4,500 m. The enhanced pulmonary vasoconstriction after NO inhibition at basal and hypoxic conditions suggests a modulating role of NOS bioactivity in the pulmonary circulation and that augmented endothelial NOS plays a counterregulatory role in the pulmonary vasoconstrictor response to acute hypoxia in high-altitude adapted Tibetan sheep.